Myelination in Pediatric
Neurology
Robert Carson MD PhD
Pediatric Neurology Resident Lecture Series
DOT 8155
09.13.2013
Goals
Review development of Myelin
 Discuss Normal Myelin Imaging
 Outline an approach to Leukodystrophies

What we will not discuss today
ADEM
 MS
 Primary inflammatory disorders of CNS
 Myelin basic science (2 weeks)
 My groundbreaking research in exquisite
detail :^(

White matter in neurodevelopment.

Abnormal connectivity may contribute to
neurocognitive deficits in:
◦
◦
◦
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Autism
TSC
Angelman’s
Periventricular
leukomalacia
(spike-timing
dependent plasticity)
(Nave, K. 2010)
Timing of myelination mirrors human
development
Cortical thickness reaches a
developmental nadir while myelin
continues to increase
Normal myelination/general MRI
patterns

Need to know what is normal to know what is
not normal.
◦ Neonate:
T1 hypo T2 hyper
◦ Fully myelinated: T1 hyper T2 hypo


T1 signal increases with increasing cholesterol
and galactocerebroside
T2 signal decreases with decreasing amount of
brain water
◦ displaced by myelin
◦ Increased length hydrocarbons and double bonds

T2 changes lag behind T1 changes
General Patterns of myelination
Rostral to caudal
 Posterior to anterior
 Central to peripheral

T1
T2
T1
FLAIR
T1
T2-FSE
FLAIR
T2-FSE
T1
FLAIR
T2-FSE
T2-FSE
T1
T2-FSE
FLAIR
T2-FSE
FLAIR
FLAIR
T2-FSE
T2-FSE
Normal Variant
FLAIR
FLAIR
T2-FSE
T2-FSE
FLAIR Signal evolution
9m
15m
2y
3y
Terminal Zones of myelination
Components of myelin:
Sheath: protein-lipid-protein-lipid-protein
 Glycolipids: glalctocerebroside, sulfatide,
cholesterol

◦ Outer layer of membrane
Long chain fatty acids (middle)
 Phospholipids:

◦ Hydrophobic, on inner membrane

Others: MAG, MOG, PLP, MBP, CNPase
Leukodystrophies

Genetic, with degeneration of myelin
sheaths in CNS (+/-) PNS
◦ Related to synthesis and maintenance of
myelin membranes.
◦ Vast majority autosomal recessive

Leukoencephalopathies: defects causing
secondary myelin damage

Diagnosis requires a clinical strategy
Clinical presentation
Insiduous, in a previously healthy child.
 Slowly progressing, may have periods of
stagnation
 Vague/progressive motor and mental
symptoms.
 Widely variable phenotypes associated
with single genetic disease
 Presents from infancy to adulthood.

Age of onset
Exam

Physical abnormalities uncommon
◦ Big head: Alexander, Canavan, megalencephalic
leukodystrophy with cysts and vanishing white matter
◦ Dysmorphic features similar to
mucopolysacharidoses: fucosidosis, MLD

Neurologic (progressive):
◦
◦
◦
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Motor (spasticity)
Changes in cognition and language
Seizures are rare
Peripheral nerve (MLD, globoid cell, hypomyelination)
Diagnosis: MRI most important test

Stepwise approach:
1. Hypomyelination?

Differentiate delayed vs. permanent with serial
MRI studies
2. Confluent, bilateral, symmetric wm lesions
c/w genetic disease vs. multifocal or
asymmetric with acquired disease
3. If confluent lesions are present, what is the
localization? (frontal, parieto-occiptial,
periventricular, subcortical, diffuse, posterior
fossa)
Abnormal MRIs are not pathognomonic

Tigroid appearance
◦ MLD
◦ Globiod cell

Sparing of U-fibers
◦ X-ALD
◦ MLD
“Nearly pathognomonic”

Alexander disease
Contrast enhancement if an
inflammatory component
FLAIR good for cysts
Additional imaging

MRS
◦ NAA elevated in Canavan
◦ Decreased NAA suggests neuronal
involvement in primary WM disease
◦ Lactate in “leukencephalopathy with
brainstem and spinal cord involvement and
elevated lactate”
◦ Other mitochondrial disorders

CT: better than MRI for calcifications
Globoid cell leukodystrophy
Swelling of optic
nerves
 Contrast
enhancement of
spinal roots
 +/- peripheral nerve
thickening

Electrophysiology

NCS
◦ Symmetric involvement of long spinal tracks
and peripheral nerves
◦ May help differentiate leukodystrophies
 Normal in X-ALD, usually abnormal with
metachromatic or globoid cell
◦ Correlates with severity of clinical disease

Evoked potentials
◦ BAER abnormal first, then SSEP lower limbs,
then MEPs of lower limbs


Tests to consider
early on in
evaluation.
Low yield of done
prior to exam and
evaluation of
imaging.
Other organ systems

Optho
◦ Cataracts
 Cerebrotendinous xanthomatosis
 Some forms of hypomyelination
◦ Cherry red spot: differentiate infantile/macrocephalic
leukodystrophies from GM2 gangliosidosis
 Such as Tay-Sachs and Sandhoff

Endocrine
◦ Addison’s disease +/- neuro invovlement in X-ALD
◦ Ovarian failure

GI
◦ Feeding and swallow issues are common.
◦ Gallbladder papilloma in MLD
Treatment
Prognosis is dismal
 Supportive care

◦
◦
◦
◦
Swallow eval/g-tube
Abx when indicated
Antispasmodics and pain control.
ACTH monitoring/stress dose steroids
Treatment Continued

Lorenzo’s oil in X-ALD
◦ Erucic and oleic acid
◦ Lowers VLC FAs
◦ Benefits asymptomatic boys

Bone Marrow transplantation
◦ Can halt progression in X-ALD, but…
◦ 2/3 boys develop cerebral disease, and…
◦ Successful only in early stages of disease.


Gene therapy
Experimental
◦ Therapeutic window is narrow
 Asymptomatic____  Too far gone
Leukodystrophies, in Summary:
Incurable with progressive motor and
mental disability
 Leukodystrophy if due to myelin sheath,
leukoencephalopathy if outside. (similar)
 White matter and gray matter disease
may overlap.
 Definitive diagnosis is challenging, though
timely diagnosis is required.

Summary continued,

Diagnosis through:
◦ Physical examination
◦ MRI imaging
◦ With help from targeted laboratory testing

Important for family counseling and
optimization of care
◦ Palliative
◦ experimental
References

Welker and Patton. Assessment of
normal myelination with magnetic
resonance imaging. Semin Neurol.
2012;32:15-28.

Kohlshutter and Eichler. Childhood
leukodystrophies: a clinical perspective.
Expert Rev. Neurother. 2011;11:1485-1496.